Autophagy is the name given to the collection of cellular processes that recycle broken and unwanted proteins and cell structures. More autophagy is a good thing, and many of the methods demonstrated in the laboratory to modestly slow aging in flies, worms, and mice involve enhanced autophagy. You might look at a recent experiment demonstrating a 10% gain in mouse life span via a narrowly targeted method of increasing autophagy, for example. Calorie restriction, the gold standard in reliability when it comes to slowing aging, depends upon autophagy: it doesn't work when autophagy is disabled.
Unfortunately, autophagy declines with age. But why? There are undoubtedly many answers to that question, a layered set of mechanisms that directly or indirectly arise from the root causes of aging, the accumulation of molecular damage as outlined in the SENS rejuvenation research proposals. In the direct case, autophagy suffers because persistent metabolic waste accumulates in lysosomes, the structures responsible for disassembling proteins and cell components. They are packed full of enzymes capable of dismantling near all of what they encounter, but near all isn't good enough over the long term. Long-lived cells in older people contain dysfunctional lysosomes packed full of a mix of hardy waste compounds collectively known as lipofuscin.
Autophagy is a complicated multi-stage process, however. Function isn't just a matter of the state of lysosomes, but also of the mechanisms responsible for flagging proteins and structures for recycling, constructing membranes around that material, and delivering the membrane-wrapped packages to the nearest lysosome. If any of that falters, then the pace of autophagy declines. The open access research here reports on an example of issues in the transport portion of autophagy, and the authors make some headway into understanding why it happens, associating it with reduced levels of KIFC3. While pinpointing age-associated changes in the expression of a particular gene is a first step, it has to be said that this rarely leads to the root cause damage without a great deal of further work.
Autophagy is a highly conserved catabolic process responsible for the delivery of cytoplasmic materials (proteins and organelles) into lysosomes for their degradation. Autophagy contributes to maintain cellular and tissue homeostasis by assuring protein and organelle quality control. A growing number of reports have linked malfunctioning of autophagy with aging, highlighting the role of autophagy as an anti-aging cellular mechanism. Furthermore, genetic inhibition of this degradative process recapitulates features associated with aging and age-related diseases. Loss of protein/organelle quality control is a universal hallmark of aging, and malfunctioning of autophagy with age contributes to this gradual accumulation of damaged proteins and dysfunctional organelles. However, the cellular and molecular mechanisms underlying this progressive decline in autophagy during aging remain unknown.
Delivery of cargo (material to be degraded) to lysosomes via macroautophagy, the most conserved and best characterized type of autophagy (hereafter denoted as autophagy), requires regulated trafficking of autophagic vesicles (AVs), the compartments where cargo is sequestered, for their fusion with lysosomes. Subcellular positioning of organelles is mainly determined by the microtubule network. Interaction of these vesicles with microtubules is mediated by motor proteins that provide the force necessary to move them along the tubulin tracks. Vesicle-associated motors are of two types depending on the direction in which the vesicle is transported: plus-end-directed motor proteins (N-kinesins) that transport vesicles toward the cellular periphery and minus-end-directed motor proteins (dynein and members of the C-kinesin family such as KIFC2 and KIFC3) that move vesicles to the perinuclear area.
The balance between active plus-end- and minus-end-directed motors bound to a vesicle's surface determines the directionality of its intracellular movement. In the case of autophagy, the balance of active motor proteins on the surface of autophagosomes has been proposed to prevent their premature or random fusion with lysosomes. In most cells, autophagosome-lysosome fusion occurs mainly in the perinuclear region where it is facilitated through both physical proximity of the organelle and slowing of vesicular trafficking. Consequently, efficient positioning of these degradative compartments in the vicinity of the nucleus in a microtubule-dependent manner is an essential step for the final completion of the autophagic process.
Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule-based minus-end-directed motor proteins, the well-characterized dynein, and the less-studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Interestingly, the motor defect seems to preferentially affect basal quality control autophagy whereas induction of autophagy by starvation restores in part association of specific motor proteins with autophagosomes and lysosomes. These findings highlight the feasibility of activating inducible autophagy in old organisms to compensate for their defective basal autophagy.